Cholesteryl ester transfer protein inhibition: from LDL lowering to dementia prevention

PURPOSE OF REVIEW: Cholesteryl ester transfer protein (CETP) inhibitors most importantly lower apoB-containing lipoproteins, yet genetic and pharmacological intervention data underscore possible benefits extending to new-onset diabetes, kidney function, septicemia and possibly dementia. To understand these sequelae, this review examines in what manner CETP inhibition reshapes lipoprotein composition, with special focus on HDL structure and function, and how these changes may underlie clinical benefits beyond consequences of LDL lowering alone. RECENT FINDINGS: Because of its central role in lipoprotein metabolism, potent CETP inhibition leads to comprehensive lipid modulation: coordinately reducing LDL-C, apoB, non-HDL-C and Lp(a) while raising HDL-C, apoA-I, preβ1 and preβ2 HDL. Beyond these changes, it remodels HDL towards a more functional cargo-carrying particle, enriched with monomeric lipid-free apoA-I, apoE, apoM-sphingosine-1-phosphate and a host of lipophilic antioxidants. These findings offer a plausible mechanistic basis for the observed reduction in new-onset diabetes, modest attenuation of kidney-function decline, preliminary sepsis-related signals and lowering of early Alzheimer's disease markers. SUMMARY: By simultaneously lowering apoB-lipoproteins and remodeling HDL to become more functional, CETP inhibition offers a coherent rationale for potential benefit across cardiovascular, metabolic, renal, immune and neurological disease. The currently ongoing obicetrapib cardiovascular outcomes trial will test whether clinical benefit follows this biology.